Abstract More Americans suffer from acute or chronic pain each year than are affected by heart disease, cancer and lung disease, and opioids represent the cornerstone of pain management. Prescriptions for opioids have tripled since 1999, paralleled by increases in opioid-related hospitalizations and deaths, and contributing importantly to the opioid epidemic. Hydrocodone, tramadol, and codeine are among the most commonly prescribed opioids, and the cytochrome P450 enzyme, CYP2D6, is central to generation of highly potent metabolites for these opioids. CYP2D6 has common genetic polymorphisms that lead to loss of function, reduced function, or increased function, conferring poor (PM), intermediate (IM), and ultrarapid (UM) metabolism phenotypes, respectively. Data suggest these three opioids should be avoided in PMs, IMs and UMs due to increased risk for poor response and toxicity, respectively. Leveraging our data from IGNITE-I, extensive stakeholder engagement, and to address the significant burden of both pain and opioid use in the U.S., we propose to test the hypothesis that CYP2D6 genotype-guided pain management leads to improved patient reported outcomes (PRO) for pain control and is cost-effective in a real-world setting. We propose a multicenter pragmatic clinical trial (PCT) of 2,100 patients with acute and chronic pain, randomized 2:1 to a genotype-guided versus usual care approach. We will enroll adults and children with cancer pain or at least 3 months of poorly controlled chronic pain and those undergoing total joint arthroplasty. Considering CYP2D6 genotype and relevant CYP2D6 inhibitor drug interactions, patients categorized as PM, IM, or UM will have a recommendation to avoid hydrocodone, tramadol and codeine. In those categorized as NM, use of tramadol will be preferred, as tramadol has lower risk of addiction than DEA Schedule II opioids. Our primary hypothesis of improved pain control with a genotype-guided strategy will be tested based on PRO of pain intensity using NIH PROMIS measures. We will utilize a multi-gene pharmacogenetic panel and also make recommendations on other drugs with established pharmacogenetic guidance. Our secondary hypothesis is that use of a pharmacogenetic panel to guide opioids and other commonly used drugs will improve patient wellbeing and reduce healthcare utilization. We will utilize validated PRO tools to assess wellbeing. Healthcare utilization and cost effectiveness analyses will be based on claims data from Medicare and Medicaid, supplemented with patient reported data on cost drivers for acute/chronic pain. We will also test physician perception of the benefit of a pharmacogenetic-guided approach to patient care. With these endpoints we can address the potential benefits of a genotype-guided approach to drug therapy that focuses on numerous stakeholders, including patients, the physicians who treat them, health systems/payers and society, relative to concerns about opioid use and addiction. To conduct this and other IGNITE-II PCTs we have assembled an outstanding team called the UF-Nemours Clinical Group, which brings to bear exceptional clinical resources.